Investigating the relationship between right ventricular size and function with pre‐eclampsia: A two‐group cross‐sectional study

Abstract Background and Aims Pre‐eclampsia is a multisystem disorder characterized by symptoms of high blood pressure and proteinuria during pregnancy. It is associated with many complications and maternal and fetal mortality. This disorder may be associated with many cardiovascular complications and affect the function of the heart. Therefore, in this study, the structure and function of the right ventricle (RV) in patients with pre‐eclampsia have been investigated using echocardiography. Methods This cross‐sectional study was conducted in Ghaem Hospital of Mashhad. Thirty‐two pregnant women, whose gestational age was 20 weeks or more, were considered as the case group after evaluating blood pressure and confirming proteinuria and pre‐eclampsia. Thirty‐two healthy pregnant women were also included in the study as a control group. The function of the RV was evaluated using two‐dimensional transthoracic echocardiography. Results Investigating the results of the study shows that in pregnant women with pre‐eclampsia, RV fractional area change, and RV strain indices have decreased significantly compared with healthy pregnant women (p < 0.05). Also, the statistical analysis shows that no significant differences were observed in the two groups in terms of echocardiographic indices E, A, É, E/É, É/Á, E/A, pulmonary artery pressure, Tricuspid Annular Plane Systolic Excursion, right ventricular diameter, and left ventricle mass index. Conclusion According to the results of the study, it can be generally said that pre‐eclampsia may be associated with changes in the function and echocardiographic indices of the RV and may result in cardiac complications.


| INTRODUCTION
Today, the most important causes of death of pregnant mothers are infection, high blood pressure (pre-eclampsia), and bleeding. 1,2 Pre-eclampsia is the most common type of blood pressure disorder during pregnancy, which is defined as a progressive multisystem with systolic blood pressure higher than or equal to 140 mmHg (or diastolic blood pressure 90 mmHg) along with proteinuria after the 20th week of pregnancy. 3 According to different studies, the prevalence of pre-eclampsia varies in different countries (from 3.3% in Australia to 12% in Bangladesh), which has the highest rate of perinatal mortality associated with adverse pregnancy outcomes. 4,5 Pre-eclampsia is the third cause of maternal mortality in the world and the second cause of maternal mortality in Iran. 6 However, recent studies have shown that the prevalence of pre-eclampsia is increasing in Iran. 4 Despite various studies, the pathophysiology of pre-eclampsia is not completely known. 7 Some studies have stated that preeclampsia is caused by maternal factors and fetal/placental factors. The incomplete connection between the placenta and the uterine wall and the lack of restoration of the spiral arteries of the decidua and myometrium in early pregnancy (weeks to months before the clinical manifestations of this disease) are known. 8,9 Lack of adequate placental blood flow leads to relative hypoxia in the trophoblast tissue, which can cause oxidative stress. 10 This alters angiogenesis within the placental villi, leading to abnormal growth of fetal vessels and resulting in abnormal vascular changes. It seems that placental secretion of antiangiogenic factors (sFlt-1 and endoglin) leads to maternal vascular dysfunction, hypertension, proteinuria, and other clinical symptoms of pre-eclampsia. 11,12 In addition, changes in cardiac function caused by increased afterload of the heart as a result of increased vascular resistance lead to the development of disease. 13 Studies have shown that focal hypertrophy caused by pre-eclampsia causes a significant increase in end-diastolic pressure, which leads to systolic and diastolic failure. 14 Pre-eclampsia is associated with various complications.
Pre-eclampsia and intrauterine growth restriction are associated with an increased risk of cardiovascular diseases for the mother in the future. Pre-eclampsia, which is associated with insulin resistance, extensive endothelial damage and dysfunction, coagulation defects and increased systemic inflammatory response, increases the risk of cardiovascular diseases. 15 Women with high blood pressure during pregnancy face an increased risk of cardiovascular diseases in the future. In particular, the history of pre-eclampsia increases the risk of venous thromboembolic diseases and hemorrhagic stroke. 16,17 Considering the limitations of the studies conducted in this regard, the purpose of this study was to investigate the relationship between the size and function of the right ventricle (RV) and pre-eclampsia.

| Ethical considerations
The procedures and objectives of the study were explained to the patient and informed consent was obtained. The participants' information was collected confidentially so as not to cause any concern for them.

| Study population and inclusion and exclusion criteria
In this case-control study, 32 patients with pre-eclampsia (after blood pressure assessment, proteinuria confirmation, and proof of preeclampsia for the case group by the doctor based on ACOG guidelines 18 ) were included as the case group and 32 pregnant women as the control group. Thirty-two members of the control group were selected from among the volunteers who referred to Ghaem Hospital of Mashhad University of Medical Sciences from July 2017 to November 2018 by nonrandom and easy sampling method. The inclusion criteria of the case group included pregnant women with a gestational age of more than 20 weeks with pre-eclampsia, sinus rhythm, and suitable echocardiographic image. Exclusion criteria were history of significant heart valve disease, congenital heart disease, history of heart surgery, history of pulmonary hypertension, history of smoking, atrial or ventricular arrhythmia, kidney diseases, lung diseases, liver diseases, history of hypertension before pregnancy, and diabetes. In the control group, healthy pregnant women with normal blood pressure and complete urine test and with a gestational age of more than 20 weeks were selected, and the people of this group were matched with the case group in terms of age and parity.

| The sample size
The sample size of this study was 32 people in each group. This was obtained by using the average comparison formula of two independent communities. Considering α = 0.05, β = 0.2, and based on the study of Çağlar et al. 19 and also considering RV basal diameter as an outcome, the sample size was calculated as 32 individuals in each group. Myocardial strain measurement is a sensitive method to evaluate cardiac function. Myocardial strain is the percentage of shape change between two areas, such as the shortening of the myocardial muscle in systole or the increase in its length in diastole, which can be calculated in three directions: longitudinal, transverse, and radial. In this study, the basis of measuring RV strain in the longitudinal direction was in the free wall and interventricular septum. 21 RVD is an indicator for measuring the diameter of the RV. The best way to measure RVD is in the RV-focused apical four-chamber view. In this study, the middle third of the RV (RV mid-diameter) was measured at the end of diastole. Normal values are in the range of 1.9-3.5 cm, and values greater than 3.5 cm indicate right ventricular dilatation (Table 1).

| TOOLS AND DEVICES
FAC is an index to evaluate the overall systolic function of the RV and is measured by calculating the difference between the right ventricular surface area in systole and diastole divided by the right ventricular surface area in diastole. Values less than 35% are considered pathological.
TAPSE is an index to evaluate the right ventricular systolic Mean PAP in this study 20 was calculated based on the following formula: 4 × (TR jet velocity) 2 + right atrial pressure.
In this formula, right atrial pressure is defined based on inferior vena cava collapsibility. In addition, TR jet velocity is the regurgitation speed of the tricuspid valve, which represents the gradient difference between the RV and the right atrium.

| DATA ANALYSIS
After collecting the data, the data were entered into SPSS software version 22. Mean and standard deviation were used to describe normally distributed quantitative data. Median and range (minimum-maximum) were reported for variables that were not normally distributed. To compare quantitative variables between groups, Mann-Whitney or t test was used. Chi-squared test was used to compare qualitative variables with each other. The Spearman correlation test was used to indicate the correlation between variables. The significance level in all tests was considered less than 0.05. All reported p values are two-sided.

| RESULTS
In this study, the average age of the participants was 31.2 ± 6.6. There was no significant difference between the two groups in terms of age (p = 0.58). Among the participants, 29 people were nulliparity and 35 T A B L E 1 Comparison of demographic status between people with pre-eclampsia and healthy pregnant people.  Table 5).
On the basis of the results of Table 6, a significant negative correlation was observed between the average RV FAC and RV strain (p < 0.001).

| DISCUSSION
According to the results of this study, the right ventricular function is study show that pre-eclampsia affects not only the left side of the heart but also the right side, which was in agreement with our study.
Although in this study, the changes following pre-eclampsia were reported in the normal range, but right ventricular dysfunction may be the cause of complications related to pre-eclampsia. In our study, there was no difference in the size of the RV between the two groups, but the RV strain was significantly lower in the pre-eclampsia group.
In the study conducted by Hassan et al. 22 in 2019, it was stated that the changes in TAPSE, ESPAP, FAC, and right ventricular myocardial function index were significantly different between the two groups, which was consistent with our study. The results of this study show that echocardiography is an important evaluation method in examining women with pre-eclampsia to prevent cardiac complications and mortality. Vaught et al. 23 in 2018 stated that women with pre-eclampsia had higher right ventricular systolic pressure levels, decreased right ventricular longitudinal strain (RVLSS), increased LA size, and increased LV wall thickness. Another important finding in this study was that 13% of women with pre-eclampsia had grade 2 diastolic dysfunction. Also, this study confirms the reduction of RVLSS, which is probably due to RV dysfunction and increased right ventricular afterload, and it was consistent with our study.
T A B L E 4 Distribution of echocardiographic indices among people with pre-eclampsia. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request. All authors have read and approved the final version of the manuscript. Milad Abouzari had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
The lead author Milad Abouzari affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.